Microbiota-derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo.

Autor: Jennis M; Cardiovascular & Metabolic Disease, Janssen R&D, LLC, Spring House, PA, USA., Cavanaugh CR; Cardiovascular & Metabolic Disease, Janssen R&D, LLC, Spring House, PA, USA., Leo GC; Discovery Sciences, Janssen Pharmaceutical R&D of J&J, Spring House, PA, USA., Mabus JR; Cardiovascular & Metabolic Disease, Janssen R&D, LLC, Spring House, PA, USA., Lenhard J; Cardiovascular & Metabolic Disease, Janssen R&D, LLC, Spring House, PA, USA., Hornby PJ; Cardiovascular & Metabolic Disease, Janssen R&D, LLC, Spring House, PA, USA.
Jazyk: angličtina
Zdroj: Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society [Neurogastroenterol Motil] 2018 Feb; Vol. 30 (2). Date of Electronic Publication: 2017 Aug 07.
DOI: 10.1111/nmo.13178
Abstrakt: Background: The diet and microbiome contribute to metabolic disease in part due to increased intestinal inflammation and permeability. Dietary tryptophan is metabolized by both mammalian and bacterial enzymes. Using in vitro, in vivo models, and clinical data, we tested whether bacterial tryptophan indole derivatives underlie the positive benefits of microbiota on inflammation that is associated with metabolic disease.
Methods: In high-fat diet (HFD)-fed mice intestinal permeability and plasma endotoxin levels were measured after indole-3-propionic acid (IPA; 20 mg kg -1 p.o. for 4 days). Tryptophan derivatives effect on permeability and gene expression were assessed in T84 intestinal cell monolayers, in the presence or absence of pro-inflammatory cytokines. Plasma tryptophan metabolites were analyzed from lean, or obese T2D subjects undergoing Roux-en-Y gastric bypass surgery (RYGB).
Key Results: IPA reduced the increased intestinal permeability observed in HFD-fed mice. Of 16 metabolites tested in vitro, only IPA, and tryptamine reduced T84 cell monolayer permeability compromised by pro-inflammatory cytokines. In T84 cells, IPA reversed the IFN-γ induced increase of fructose transporter SLC2A5 (GLUT5) mRNA, but not induction of inflammatory or metabolic genes. In obese subjects, IPA levels were reduced relative to lean counterparts, and these levels were increased by 3 months after RYGB.
Conclusions and Inferences: The novel findings are that obese subjects have lower levels of IPA, a solely bacterially derived tryptophan derivative, and IPA improved intestinal barrier function in vitro and DIO mice. Reduced plasma IPA levels and reversal by surgery may be a consequence of intestinal indole-producing microbiota but underlying mechanisms warrant further investigation.
(© 2017 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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